This proposal addresses two inter-related topics of great importance to the health and development of girls in our nation: Turner syndrome (TS) and puberty. TS, a common genetic disorder, is due to the absence of part or all of one X chromosome in a female. Girls with TS typically manifest a behavioral profile with relative strength in verbal ability, relative weakness in visuospatial and executive function abilities, and impaired social cognition and behavior. Most girls with TS also fail to develop normal ovarian tissue and thus have reduced endogenous estrogen throughout their lifetimes. As a result, these girls receive estrogen treatment to induce puberty as standard medical care. However, estrogen treatment in TS usually begins at 12-14 years, which is considerably later than the average age of puberty in healthy control (HC) girls (~10 years). Human cognitive and behavioral development is profoundly influenced by puberty, a maturational period associated with dynamic changes in brain structure and function in HC girls and boys. However, anatomic and functional brain correlates of human puberty are currently not clear and thus, our ability to elucidate links between brain and behavior during this critical period is limited. Adding to the complexity of this research area are data indicating that puberty-associated neurodevelopmental changes are sexually dimorphic, thus necessitating careful, independent investigation of brain-behavior associations in both males and females. Using multilevel methods including neuroimaging, cognitive-behavioral evaluation and parent-of-origin genotype, the longitudinal study proposed here will permit an in-depth examination of gene-brain-behavior associations on a developmental basis in sixty 9 to 16 year old girls with TS as they begin estrogen and transition into puberty and adolescence. Because the dates and doses of estrogen treatment will be known for our subjects, we will be able to directly test novel hypotheses related to the age of initiation and duration of estrogen therapy on brain and behavioral development. Further, we will compare and contrast our TS cohort with a group of sixty age and sex-matched HC girls, who will also be studied on a longitudinal basis. (All subjects will be evaluated annually at four time points.) Accordingly, the findings from this study will provide wholly new information about the neural effects of estrogen in TS, and how brain and behavioral development during puberty in TS is similar to, or differs from that seen in typical development. A particular focus will be on distinguishing puberty-associated changes in brain and behavior that are estrogen-sensitive from those that are estrogen-insensitive. By bringing together experts in pediatric psychiatry, endocrinology, neuroimaging, neuropsychology and development, and advanced biostatistics, the research we will perform in the next grant period has the potential to significantly enhance medical, behavioral and educational practices for girls with TS. Findings from this project will also inform a broad range of key health issues relevant to child development, particularly with regard to the complex links between brain development and behavior in adolescence. ! PUBLIC HEALTH RELEVANCE: In this project, we will follow a large group of children with Turner syndrome, a common genetic condition affecting only girls, before and after they receive estrogen replacement therapy to induce puberty. The proposed study offers unique opportunities to advance our understanding of how puberty/estrogen influences adolescent brain development in young girls with TS. This knowledge will be of utmost importance to medical practitioners who work with TS patients but also has the potential to inform a broad range of key health issues relevant to child and adolescent brain and behavioral development.